Venous thromboembolism (VTE) is a common disease and an important public health problem. Both environmental and genetic risk factors have been documented to be important and evidence from recent studies suggests gene-environment interactions in the etiology of VTE. Previously identified genetic variants only explain a small proportion of VTE risk. The objective of the proposed study, from a new investigator, is to identify variants in genes involved in important pathways of the hemostasis system that contribute to the risk of VTE and the variation of its intermediate phenotypes. The VTE phenotype derives from the Longitudinal Investigation of Thromboembolism Etiology (LITE), which includes the Atherosclerosis Risk in Communities (ARIC) and the Cardiovascular Health Study (CHS). An anticipated 3447 SNPs in 116 candidate genes, selected from coagulation, platelet aggregation, and acute phase response signaling pathways, are the main focus of the application. These SNPs are measured on the cohorts of the Candidate-gene Association REsource (CARe) Study, which includes the ARIC, CHS, Multi-Ethnic Study of Atherosclerosis (MESA), and Framingham Heart Study (FHS) cohorts. Utilizing the genotype and phenotype resources from the CARe and ARIC Studies, we propose four aims: 1) To perform longitudinal genetic association analyses between the selected candidate gene SNPs and VTE in the white participants of LITE, including at least 14,841 participants at risk for VTE at baseline and 489 VTE cases identified during 16 years of follow-up. This will include Individual SNP analysis, tests of gene-gene and gene-environment interactions, and a pathway-based approach. 2) To perform genetic association analyses between the selected candidate gene SNPs and important intermediate phenotypes related to VTE in at least 10,279 whites and 3680 African Americans of the ARIC cohort. The intermediate phenotypes include plasma levels of factor VIIIc, von Willebrand factor, and activated partial thromboplastin time. 3) To test for replication of significant genetic associations with VTE using a Mayo Clinic VTE study (1500 VTE cases and 1500 controls), or with the intermediate phenotypes using other cohorts in the CARe Consortium including the FHS, CHS, and MESA, or the Caerphilly Study, a UK population-based epidemiological study. 4) To saturate genes identified in Aim 3 by genotyping additional SNPs in LITE for VTE and in ARIC for the intermediate phenotypes. Our study will provide important new information on the genetic determinants of VTE and its intermediate phenotypes, potentially providing new opportunities in the prevention or treatment of VTE. PUBLIC HEALTH RELEVANCE: The proposed study will provide greater understanding of the genetic determinants of venous thromboembolism and it intermediate phenotypes at the population level and potentially provide new opportunities for the prevention or treatment of venous thromboembolism.